A Faustian bargain

Natural selection has inflicted one disease on humanity in order to protect it from another

SIMPLE genetic diseases—those caused by the malfunction of a single sort of gene—are rare, and the explanation for their rarity is easy. People who suffer from them are at a marked reproductive disadvantage, so the disease-causing genes do not tend to get passed from generation to generation. Like most rules, however, this one has an exception.

The exception is sickle-cell anaemia, an illness caused by a fault in one of the genes for haemoglobin, the oxygen-carrying protein that gives blood its colour. It is suffered predominantly by West Africans and their descendants in other parts of the world. The reason is that, while a double dose of the faulty gene (one from the mother and one from the father) inflicts the disease, a single dose confers protection against one of West Africa's top killers—malaria. People with a single dose of the faulty gene produce enough normal haemoglobin to carry oxygen around their bodies, but the presence of faulty haemoglobin somehow inhibits the growth of the parasites that cause malaria. In evolutionary terms, this protection outweighs the fatalities imposed by the anaemia, so the faulty gene is preserved in the population.

For several years, researchers have suspected that something similar is true of cystic fibrosis in northwestern Europeans and their descendants. This disease, like sickle-cell anaemia, is usually fatal. But it is also—again like the anaemia—suspiciously common (in Britain, for example, it afflicts one child in 2,500). Unlike sickle-cell anaemia, however, no one has been able to work out which infection the possession of a single dose of cystic-fibrosis gene protects against.

Gerald Pier, of Harvard Medical School in Boston, and his colleagues, think they have the answer: typhoid fever. Their research, published in this week's Nature, studied the relationship between Salmonella typhi, the bacterium that causes typhoid fever, and the protein which, when faulty, causes cystic fibrosis. They showed that S. typhi uses the healthy version of this protein (known as cystic fibrosis transmembrane conductance regulator, or CFTR) as an entry point into the gut cells that it infects. They also showed that cells which produce a mixture of healthy and unhealthy CFTR are much less likely to become infected.

CFTR, as its name suggests, sits in the outer membrane of a cell. Its job is to regulate the passage of chloride ions (electrically charged chlorine atoms) across that membrane. When it goes wrong, the local salt balance is upset and mucus tends to build up around the cells in question (particularly those in the gut, lungs and pancreas) with ultimately fatal results. Exactly how CFTR allows S. typhi to get into a cell is not yet clear, but the bug seems to have a spot on its surface that binds to part of the protein. This anchor presumably allows it to penetrate the membrane more easily. Changing the chemical composition of the anchor (which is what happens as a result of the faulty gene), prevents the bacterium from sticking to it.

Dr Pier and his team began their work by looking at cells cultured from a cystic-fibrosis patient. Some of these cells were left alone, while others had DNA for the healthy protein injected into them in order that they should produce normal CFTR as well. The researchers found what they had hoped: the injected cells took up between two and ten times as many S. typhi as those without the normal protein.

To make a more precise model, the group then genetically engineered two strains of mice—one to contain normal CFTR genes and the other to contain the faulty version. Mice with a mixture of the two genes were found to be protected against S. typhi infection. These mice took up 86% fewer bacteria into their gut cells than those that had only the healthy genes—greatly reducing the chance of the bacteria getting a proper grip.

It seems, therefore, that having a mixture of healthy and faulty genes (and therefore producing a mixture of healthy and faulty CFTR proteins) probably does protect against typhoid fever. It may not be much comfort to the parents of children with cystic fibrosis to know that they (being carriers of the faulty CFTR gene) will never catch an infection that is now, in any case, quite rare in the West. But it is a neat example of how modern life has rendered an evolutionary adaptation from the past irrelevant.